User blog: Meguid El Nahas
So the SHARP study is also negative as far as the impact of STATINS ON CKD PROGRESSION...as it is on other major outcomes such as hospitalisations and mortality in CKD.
YET...IT IS OVERALL SPAN AS A STUDY THAT SHOWED THAT STATINS REDUCED MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) IN CKD PATIENTS....
THIS IS TOTALLY MISLEADING...AS:
SHARP FAILED TO SHOW ANY IMPACT OF STATINS ON:
1. All cause mortality
2. Vacsular/CVD Mortality
3. Non Vascular mortality
5. CAD and its complications
6. Strokes of unknown causes
AND NOW...as previously suggested CKD AND ITS PROGRESSION.
SO WHY IS SHARP SPUN TO NEPHROLOGISTS AS A POSITIVE STUDY THAT REDUCES CVD?
AND WHY DO NEPHROLOGISTS BELEIVE SUCH SPIN?
1. Clearly many Nephrologists are gullible...
2. Many Nephrologists dont know how to read a publication/report critically...
3. Most Nephrologists know little about statistical analyses...
4. Those with a vested interest in a study positive outcomes, including BIG PHARMA, are smart...and take advantage of our shortcomings and fool us to beleive in what is in their interest...
Based upon the fact that SHARP showed BY THE INAPPROPRIATE USE OF SOFT ENDPOINTS AND COMPOSITE ENDPOINTS:
a. A reduction in THE SOFT ENDPOINT OF vascular revascularisation; a procedure freely and subjectively undertaken in many countries, including the USA, by interventionists with little justification, indications or lasting beneficial outcome. In favour of such assumption is the absence of any IMPACT of statins on harder CAD endpoints such as myocardial infarction or coronary related mortality...!!!???
b. A Reduction in ischemic/non-hemorragic strokes; whilst other strokes were not affected AND more significanlty the hard endpoint of death from ischemic strokes is NOT affeceted...!!!!
Also to bare in mind, STATINS INCREASE THE INCIDENCE OF HEMORRHAGIC STROKES as shown in numerous studies including AURORA but also in the recent analysis of the Framingham Heart Study (FRS) where statins increased the risk of cerebral bleeds...
c. SHARP innapropriately used COMPOSITE ENDPOINTS, mixing meaningful and irrelevant outcomes in order to rely on the meaningless (revascularisation procedures) to give the impression that the meaningful MACE are improved on Statins...WRONG AND MISLEADING and a poor and ill informed use of composite endpoint in clinical trials:
In fact, there is a complete disconnect in SHARP between the chosen soft endpoints coronoray revascularisations and ischemic stroke events and the HARD ENDPOINTS related to these such as hospitalisations or MORTALITY....?!
ALTOGETHER SHARP IS A NEGATIVE STUDY SHOWING NO MEANINGFUL EFFECT OF STATINS ON HOSPITALISATIONS OR ANY TYPE OF MORTALITY IN CKD PATIENTS....IT IS BEING SPUN TO CONVINCE US OTHERWISE...SO BEWARE...AS SUCH SPIN HAS ALREADY FOOLED MANY INCLUDING THE KEY OPINION LEADERS WHO DRAFT NATIONAL AND INTERNATIONAL GUIDELINES...BUT IT SHOULDNT FOOL YOU!
I have been practicing Medicine and Nephrology for 40 years.
It occured to me that true and major breakthroughs in the management of CKD have been few and far between during these 40-50 years.
In fact, when I started practicing Nephrology and until recently CKD meant: Glomerulonephritis, Pyelonephritis, Reflux nephropathy and Dysplastic Kidney Disease (later called CAKUT), Hypertensive nephrosclewrosis, diabetic nephropathy and PKD (ADPKD).
CKD in the community, with its "epidemic" and all that is the brainchild of KDOQI and KDIGO CKD definitions and classifications that have created a monster out of the decline in kidney function in the over 50 and 60 years...This I will not comment upon here as I have already on many occasions only to dismiss this community CKD (cCKD) and all its ills as the takeover by epidemiologists (rather biostatisticians) and the ones I call "Spreadsheet Nephrologists" of our beautiful profession and specialty...
Back to true Nephrology, and true CKD (previously called Chronic renal failure [CRF]), no biostatistians or epidemiologists needed to tell us that its incidence and prevalence have somewhat increased due to ageing and the associated increase in hypertension and DM - related CKD. Also, more and more elderly present with atherosclerotic and ischemic nephropathies.
But my point here is:
40 years on, has there been any major therapeutic breakthrough in the management of true referred CKD (rCKD)?
My answer is NO:
1. When I started we had a range of anti-hypertensive agents including diuretics and beta-blockers. They treat hypertension effectively with a few other classes of agents including RAAS inhibitors. What matters is the BP control regardless of the agent or class of agents used.
2. For GN primary or secondary, we had immunosuppression with steroids +/- azathioprine/cyclophosphamide. Steroids and Azathioprine/cyclophosphamide remain the cornerstone of the management of GN.
3. For Reflux nephropathy/Pyelonephritis, we had antibiotics prophylactically or otherwise, we still have them, although the clever bacteria we treat or trying to prevent have learned to become more resistant...
3. For ADPKD, still the same treatment, early diagnosis and treatment of hypertension.
4. For HT nephrosclerosis, control hypertension and nil else...
5. For DN, control hypertension and not much more...
So little therapeutic advances that proved superior to those we used 40 years ago...in spite of almost 40-50 years on unabated research and promises to slow CKD progression:
Anti-platelets, anticoagulants, prostaglandins manipulations, nitric oxide manipulations, cytokines, chemokines and growth factors antagonsists, not to mention a number of anti-fibrotic strategies including pirfenidone, collagen synthesis and deposition inhibition etc...and of course TGF-beta1 remains the most fibrogenic of growth factors...and we still have not managed to translate that knowledge (20 years old by now) to the bedside...???!!!
Very disappointing...and worth questioning whether the R&D as well as translation strategies we are relying upon to discover new and more effective therapies to slow CKD progression are effective or at least cost-effective?
May be thats why Nephrologists started to look elsewhere, came up with a new definition of CKD, created new detection tools (eGFR formulas), teamed up with biostatisticians, screened everybody, generated a "CKD Epidemic" to give themselves a new impetus and generate more attention to their dormant specialty...?!
This month in the Lancet:
An editorial by Farhat Yaqub on:
Rana Dajani and teh Ethics of Stem cell Research in the Middle East.
The editorial highlights Dr Rana Dajani elevated position in medical and biology research with emphasis on her work in genetics but also the potential of stem cell research to treat many genetic and rare diseases.
Dr Dajani who works at the Hashemite University in Jordan has initiated working and advisroy partiers to explore the potential of stem cell research therapy in medicine and has involved physicians, scientists but also religious and legal experts.
This is a very important step forward in the ethics and governance of medical research in the Middle East and in aprticular in research and potential treatment involving stem cells.
Stem cell therapies like all medical innovcative interventions require considerable governance to translate from basic science to the bedside. Whilst such governance and guidance are often in palce in high economies, the translation of medical adsvances into clinical practice often lacks rigorous governance and good clinical practice (GCP) in emerging countries.
All too often patirents are treated with experiemntal intyerventions before such GCP related steps are implemented and even before ethical and IRB approval or even consideration. This has to be subject of grave concern as patients with geentic conditions, those with orphan and rare disease and others with a range of metabolic abnormalities potentially amenable to stem cell therapies have to be protected against malpractices before they benefit from good practices...
They need to be protected from:
1. being used as guineapigs for greedy scientists and investigators
2. being exploited, and their suffering, by money seeking investigators, physicians and Pharma.
3. being exposed to potential risks before benefiting from potential advances.
4. being duped to beleive their are treated with proven interventions...whe in reality they are subject of research into unproven interventions...after all that is the essence of clinical trials: to Test and Unproven intervention that seems promisiiong...as if it was of proven benefit, it would no longer be ethical to deny its benefits from a control group given placebo....
5. being subjects in poorly controlled and badly conducted "clinical research" that ultimately will yeild no meaningful outcome other than boost the income of the sponsors and investigators of such research...
More than in any other field of medicine, stem cell researchj and therapy has raised considerable hopes and expectations amongst the medical profession and those suffering from a wide range of diseases from Daibetes mellitus, heart failure, multiple sclerosis to spinal injury and kidney diseases, but the road ahead is long....and in emerging countries the risk of exploitation is high, thats why the work of people like Rana Dajani has to be commented and followed with great interest.
This Blog aims to raise awareness of the importance of Good Clionical Practice and the Governance and Ethics of Medical Research in Emerging countries;
IT IS NOT ALWAYS AS GOOD AND ETHICAL AS WE WOULD EXPECT...
In this field, as in many others, conflicts of interest between researchers, physicians and Industry is a threat to research and advances integrity. Tight policies have to be in place to safeguard medical practice and patients.
In this field, examples are common of abuse and malpractices that dont live up to ethical or moral expectations:
In this field of stem cells, less regulation may be warranted for basic research but more regulation has to be implemented acroos the board with special attention to emerging countries when it comes to teh translation of basci scientific advances to the bedside and patients' care:
FINALLY WE NEED TO GUARD OURSELVES AND OUR PROFESSION AGAINST USING PATIENTS HOPES AND EXPECTATIONS, TO GENERATE UNWARRANTED HYPE THAT AIMS TO PROMOTE THOSE WHO USE THE POTENTIAL NEW THERAPIES, SUCH AS STEM CELLS, IN UNETHICAL AND IMMOARL WAYS:
PROFESSOR RICHARD GLASSOCK WROTE:
New NICE CKD Guidelines
On July 23, 2014 the National Institute for Health and Care Excellence (NICE) of the United Kingdom released its new 2014 guidance for Chronic Kidney Disease (CKD). This new version updates and revises guidance distributed in 2008.
NICE was one of the first to subdivide CKD Category 3 (eGFR 30-59ml/min/1.73m2) into Categories 3A (eGFR 45-59ml/min/1.73m2) and 3B (eGFR 30-44ml/min/1.73m2) and to add proteinuria (defined as a urinary albumin to creatinine ratio >30mg/mmol) using the KDOQI 2002 classification schema as its base. This new iteration is based extensively upon the 2013 KDIGO CKD classification system.
Many changes have been made and in the interest of space I will comment on only a few. It is worth reading the original at http://www.nice.org.uk/Guidance/CG182.
First, like KDIGO they have reduced the UACR threshold for CKD from 30mg/mmol to 3mg/mmol, embracing the controversial issue of isolated “microalbuminuria” as CKD. I do not happen to agree with this step; but it is generated from the KDIGO 2013 CKD classification system, without a well-reasoned rationale. Prospective studies demonstrating benefits compared to risk for using this threshold is currently lacking.
Second, they have adopted the CKD-EPI creatinine equation (using IDMS standardized serum creatinine values and after adjustments for black vs non-black race and gender) as the standard way of determining eGFR and suggest that all clinical laboratories (including those that are hospital-based based) utilize this equation when reporting eGFR. I have concerns in that the CKD-EPI equation was developed by epidemiologic studies primarily in clinically stable outpatients. The instability of hospital inpatients and the impact of acute and chronic illness on endogenous creatinine generation may make the CKD-EPI equation a less reliable and accurate tool in hospitalized patients, especially those in an ICU environment.
Third, like KDIGO the NICE guidance suggests that eGFR- cystatin C be used as a “confirmatory” test in the subset of subjects with an eGFR-creatinine of 45-59ml/min/1.73m2 who have an UACR of <3mg/mmol and that CKD NOT BE DIAGNOSED in such patients who have an eGFR-cystatin C of >60ml/min/1.73m2. Since eGFR- cystatin C is no more accurate a tool than eGFR- creatinine in providing an accurate estimate of true or measured GFR, any improved identification of CKD (based on prognosis rather than a departure from normality of GFR) is likely to be due to the non-GFR determinants of eGFR-creatinine and/or cystatin C bearing on adverse events, such as CV disease.
Fouth, the guidance suggests that “opportunistic screening” for CKD (presumably during encounters with the health care system), be offered to those at increased risk of CKD, regardless of age (such as diabetes, hypertension, CV disease, multisystem disease or a family history of CKD). Importantly, older age per se is not regarded as a sufficient reason for such testing. This differs dramatically form recommendation for US organization, such as the National Kidney Foundation. Wisely, NICE took no position on population-based screening for CKD--- a position generally agreed upon by other agencies such as the US Preventative Services Task Force.
Finally, and most disappointingly from my perspective, NICE did not suggest that the eGFR thresholds for defining CKD be age calibrated. This position is identical to that of KDIGO 2013 and both systems ignore the normal decay of renal function with organ senescence. This mistake, in my view, will lead to an ever-increasing prevalence of falsely defined CKD as the population ages, and will lead to unnecessary referrals and testing in the older adult without abnormal albuminuria. As stated previously and until more prospective interventional information is available, I prefer to define abnormal albuminuria as >30mg/mmol persisting for 3 months or more, but I fully recognize that this is a minority position at present.
Notwithstanding these criticism of the NICE 2014 guidance, the overall document is well-written in clear and easily understandable language. I agree with many things in the document, such as when to employ an accurate and precise measured GFR, use of reagent strips to define haematuria instead of urinary sediment, how to identify progression of CKD based on repeated eGFR determinations and not recommending low-protein diets (<0.6-0.8gg/kg/d) in patients with CKD, and scrupulously avoiding the use of combinations of RAS antagonists in people with CKD.
I am confident that these new guidance statements from the highly-regarded NICE organization will elicit an interesting and informative debate in the months ahead. I look forward to reading the comments of others in this BLOG space.
Richard J. Glassock, MD
Laguna Niguel, CA
July 29, 2014
Experiences Obtaining Insurance After Live Kidney Donation
The impact of kidney donation on the ability to change or initiate health or life insurance following donation is unknown. To quantify this risk, we surveyed 1046 individuals who donated a kidney at our center between 1970 and 2011. Participants were asked whether they changed or initiated health or life insurance after donation, and if they had any difficulty doing so. Among 395 donors who changed or initiated health insurance after donation, 27 (7%) reported difficulty; among those who reported difficulty, 15 were denied altogether, 12 were charged a higher premium and 8 were told they had a preexisting condition because they were kidney donors. Among 186 donors who changed or initiated life insurance after donation, 46 (25%) reported difficulty; among those who reported difficulty, 23 were denied altogether, 27 were charged a higher premium and 17 were told they had a preexisting condition because they were kidney donors. In this single-center study, a high proportion of kidney donors reported difficulty changing or initiating insurance, particularly life insurance. These practices by insurers create unnecessary burden and stress for those choosing to donate and could negatively impact the likelihood of live kidney donation among those considering donation.
See Original Source http://goo.gl/2k87QW
Sadly this is most likely the consequence of the eGFR-CKD hysteria...those who donate and end up with an eGFR<60 are automatically labelled as suffering from CKD and consequently have difficulties getting life insurances.
It is high time that this eGFR-CKD mislabelling of these otherwise healthy individuals is addressed.
It is high time it is recognised that their life expectancy is in some instances higher than the general population, due to better health and better follow-ups.
It is also high time that mislabelling, otherwise healthy individuals, as suffering from CKD based on an eGFR calculation is stopped if we dont want to put people off kidney donation.
The eGFR based CKD classification of otherwise normal older people and kidney donors with eGFR<60 as suffering from a disease (CKD3) is one of the sad consequences of the eGFR-CKD hysteria and bandwagon that need to be stopped at once.
Nephrology practice, research and publications seem to have been highjacked by spreadhseet nephrologists and biostatisticians who are changing the face of Nephrology and its practice.
They have created a bubble with CKD…; global epidemic of CKD....that never was...Global healthcare threat....that is misunderstood and misrepresented...not to mention the medicalization of the normality of millions of asymptomatic mostly older individuals who suddenly find themselves labelled as suffering from a disease, CKD, they never had…
The Spreadsheet nephrologists and their Biostatistician colleagues went to action some 10-12 years ago, armed with a new CKD classification (KDOQI 2002) based on estimated GFR (eGFR), the new holy grail of Nephrology….
The KDOQI and more recently the KDIGO CKD classifications are based on eGFR and false assumptions emanating from spreadsheet nephrologists and biostatisticians misinterpretation of insufficient and seriously flawed and invalid data.
Most of the KDIGO CKD Cohorts, upon which the new 2012 proposed classification is based, are seriously flawed:
Individuals all over the world, in excess of a million... tested only once, inaccurately with non validated or standardised biochemistry, with wrong assumptions of chronicity who have their data put on spreadsheets and given to biostatisticians sitting in front of their computers crunching these inaccurate data...to come up with all sorts of prediction models and false assumptions....
“Epidemic of CKD”....Wrong!....just an epidemic of misleading biostatistics in an ageing population....
eGFR/Albuminuria powerful and independent predictors of death...Wrong!....just a misinterpretation of the data....data that even those who have put it forward have argued plausibly that it was weak, flawed and not validated to predict mortality or cardiovascular disease....
But this doesnt deter the spreadsheet nephrologists and the Biostatisticians who carry on regardless...and claim in one paper that mortality increases with CKD regardless of individuals' age....
Only to contradict themselves, using the same biostatistics and spreadsheets...., to say that life expectancy is not different between individuals with normal renal function and those with reduced GFR (down to 45ml/min):
Clearly, premature conclusions regarding the incidence, prevalence and prognosis of CKD based on false and invalid assumptions made by spreadsheet nephrologists and biostatisticians who probably never saw a CKD patient beyond their computer spreadsheet and databases…
Same with eGFR, an approximate calculation of true GFR, that is at best confusing and at worst misleading:
eGFR is at the basis of the false assumptions made about CKD prevalence and prognosis.
Based on eGFR <60, millions have CKD; when in reality the measure is at best imprecise and at worst inaccurate...
Mostly, labelling seemingly healthy older individuals as suffering from a disease, CKD, they never had...they just have a slow and expected decline in their organ function including age-related decline in kidney function…a dangerous and misleading medicalization of an growing ageing population…with unwarranted consequences!?
Then, the spreadsheet nephrologists and their biostatisticians tells us that eGFR, with its endless variety of formulas, predicts all sorts of ills...cardiovascular disease (CVD), mortality etc...when in reality all it does...badly...is reflect the prognostic value of its components:
Mostly, Age and Gender, those two integral part of the eGFR formulas and the strongest predictors of CVD and death....
And serum creatinine, which along with Cystatin C, are better predictors of outcomes than their unnecessary formulation into an eGFR:
In fact, eGFR adds little if nothing to standard CVD and mortality prediction models such as the old fashion Framingham Risk Score (FRS):
Beyond the spreadsheet nephrologists, eGFR offers little to jobbing clinical nephrologists:
1. It underestimates true GFR in early CKD
2. It overestimates GFR in late CKD
3. It is useless at reflecting CKD progression
4. Inaccurate in timing RRT as serum creatinine can decrease by up to 20% in CKD5 due to ESRD and its metabolic consequences.
5. Unhelpful in AKI; as useless and not applicable in absence of a steady state
6. Unhelpful in renal transplantation, confounded by medication
So who is eGFR for, other than spreadsheet nephrologists and biostatisticians…???
Perhaps, non nephrologists who don't know the normal range of serum creatinine and make the wrong assumptions based of normal renal function faced with serum creatinine levels that are raised for a given age…mostly older individuals…better knowledge of serum creatinine norms, their population based percentiles and distribution would suffice;
if not just dividing 1 by the serum creatinine level (mg/dl) would give the non-nephrologists a useful enough approximation of GFR to adjust drug dosage and avoid unnecessary nephrotoxicity, without the false pretense of accurate GFR estimation by eGFR...
But perhaps, and after all….eGFR may also be helpful to clinical nephrologists..., as by playing around with formulas they can cure people from CKD…if you have CKD with the MDRD formula, then apply CKD EPI and you are cured…if not try the Virga equation...; after all the prevalence of CKD in the community varies from 5.8% (MDRD), to 3.6% (CKD EPI) to even 1.8% (Virga)…in one stroke the prevalence of CKD can be reduced to a quarter of its original value with the help of...eGFR formulas…and... biostatisticians!!!! ;)
Longitudinal changes in estimated and measured GFR in type 1 diabetes.
Estimation of GFR from serum concentrations of creatinine and cystatin C has been refined using cross-sectional data from large numbers of people. However, the ability of the improved estimating equations to identify changes in GFR within individuals over time has not been rigorously evaluated, particularly within the normal range of GFR. In cross-sectional and longitudinal analyses of 1441 participants in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study with type 1 diabetes, we compared GFRestimated from creatinine (eGFR(Cr)), cystatin C (eGFR(Cys)), or both (eGFR(Cr+Cys)) with iothalamate GFR (iGFR), including changes in each over time. Mean (SD) iGFR was 122.7 (21.0) ml/min per 1.73 m(2). In cross-sectional analyses, eGFR(Cr+Cys) estimated iGFR with the highest correlation (r=0.48 versus 0.39-0.42), precision, and accuracy. In longitudinal analyses, change in eGFR(Cr+Cys) best estimated change in iGFR; however, differences between estimates were small, and no estimate accurately classified change in iGFR. Over a median 23 years of follow-up, mean rate of change in eGFR was similar across estimates of eGFR(Cr), eGFR(Cys), and eGFR(Cr+Cys) (-1.37, -1.11, and -1.29 ml/min per 1.73 m(2) per year, respectively). Associations of BP and hemoglobin A1c with change in eGFR were strongest for eGFR(Cys) and eGFR(Cr+Cys). Together, these results suggest that the addition of cystatin C to creatinine to estimate GFR may improve identification of the causes and consequences of GFR loss in type 1 diabetes, but may not meaningfully improve the tracking of GFR in clinical care.
Comments from Professor Pierre Delanaye:
An extremely interesting study as the authors looked at the patients with type 1 DM with a "normal" GFR (average 123 ml / min) and changes in GFR with time comparing measured GFR to eGFR.
977 patients had GFR measured by iothalamate at least more than once on an average of 3.1 years (average between 1 and 6 years follow-up). The formulas used are those of the CKD-EPI consortium. The results show that all formulations (eGFR) are not suitable to reflect the slope of true GFR decline with time.
Cystatin C based equations brings a little more compared to creatinine based equations but thats probably clinically insignificant.
The most illustrative result seems to me that: 297 patients had a measured GFR that decreased by >15 ml/min.
By contrast:CKD-EPI based on creatinine showed that only 46 patients had a GFR decline of >15 ml/min, CKD-EPI based on cystatin C gave 54 patients and CKD-EPI combining Cr + CysC gave 47 patients.
The agreement between measured GFR and eGFR was poor in terms of revealing individuals with T1DM who had a decline in GFR.
This implies that whilst eGFR formulas may agree with measured GFR to a certain extent in cross-sectional studies, they are very poor in estimating changes in GFR with time.
This important observation confirms a growing body of evidence that the estiamtion of changes in GFR with time whether in longitudinal observational studeis or in interventions clinical trials is misleading.
eGFR in this study serioulsy underestimated patients with progressive decline in kidney function.
This agrees with the observationsmade by Ruggenenti et al in 2012 who showed that in patients with ADPKD the MDRD as well as the CKD EPI eGFR formulas underestimated GFR changes by 50%. The authors stressed that direct kidney function measurements by appropriate techniques are needed to adequately evaluate treatment effects in clinics and research.
It is time to review our underestanding and evaluation of the progression of CKD and related progression intervention trials relying on eGFR, with a critical eye based on the above observations.
Increasingly, I ask myself what is eGFR useful for...????
Not accurate in individuals with normal or near normal GFR as they underestimate true GFR...
Not accurate in CKD4-5 as they overestimate true GFR...
Not accurate in predicting CKD progression as they underestimate progressors...
Not accurate in predicting timing of RRT...
Useless in AKI...
Not very helpful after renal transplantation...
It seems to me that eGFR is only useful for "Spreadsheet Nephrologists/Biostatisticians" who want to publish weak and unvalidated data dressed up as "high science"...in Nephrology journals that are too uncritical to accept their manuscripts...
For me as a clinical nephrologist, I can live happily without eGFR!
DR SAMAH IDRISS REPORTED FROM EDAT-ERA 2014:
EUROTOX GRAND SESSION
PROF R Vanholder and G. Glorieux
Uremic toxins are more like established Gut Kidney axis with effect on mechanisms with impact on survival and quality of life of CKD patients :
progression of CKD
Protein bound uremic toxins :
1-Hippurate ( inhibits uremic glucose utilization and involved with muscle weakness in uremic patients, also in CSF responsible for neurological symptoms in old literatures !!!! )
New studies on Rat models of CKD shows that it accelerate tubular injuries , glomerular dysfunction and glomerulosclerosis..
2- Phenylacetic acid impairs macrophage functions and involves in inflammation -oxidative burst theory and inhibiting iNOS .
GUT KIDNEY AXIS determinants :
Nutrient availability (Carbohydrates and Nitrogenous molecules ) +colonic transit time ( specially with HD patients having prolonged colonic transit time )+ composition of colon microbiota (CKD alters intestinal flora )
Possible interventions :
Protein restriction(CKD 3-5 ND)
food supplement (pre and pro synbiotics ) !!!
pharmacological therapies to alter GI physiology(acarbose)
Avoiding therapies slowing down the transit time /
removal of protein bound toxins by combined fractional plasma separation and adsorption techniques (FRAD vs HF HD)
As many are of microbial origins so to prove causal relations for sure ... we should focus on intestinal generation , tubular secretion ,novel approaches in dialysis to decrease the circulating levels .
UREMIC TOXINS...THE LOCH NESS MONSTER OF NEPHROLOGY...REARS ITS HEAD EVERY NOW AND THEN...AND THEN DISAPPEARS WITHOUT TRACE OR IMPACT....WHEN WILL THOSE WHO SEARCH FOR THE HOLY GRAIL OF UREMIA TO REALISE THAT CKD IS NOT A SINGLE MOLECULE DISEASE BUT INSTEAD...A COMPLEX MULTISYSTEM...MUTLI-MEDIATORS...INTER-RELATED SYSTEMIC DISEASE....
I RECALL THE LATE PROFESSOR JONAS BERGSTROM IN THE 70-80s...SEARCHING FOR THE UREMIC TOXIN(S)...IN THOSE DAYS...MIDDLE MOLECULES...FOR SOME REASON...NOT SMALL...NOT LARGE...BUT MIDDLE MOLECULES...WAS THE ANSWER TO ALL OUR TROUBLES WITH UREMIA...
HE LIVED....PUBLISHED...AND DIED...AND MIDDLE MOLECULES ADDED NOTHING BUT CONFUSION TO NEPHROLOGY...
I FEAR THE SAME MAY BE SAID ABOUT PROF VANHOLDER ONE DAY...I SINCERELY HOPE TO BE PROVED WRONG...
THE URMEIC TOXINS CHASERS ARE CHASING RAINBOWS...
OR THE LOCH NESS MONSTER (please note that I am on holiday near a Scottish Loch...hence this analogy...)
PROFESSOR PIERRE DELANAYE WROTE FROM THE EDTA-ERA CONGRESS IN AMSTERDAM:
Le Docteur Block, bien connu pour ses nombreuses études dans le domaine CKD-MBD, a montré les premiers résultats avec un nouveau chélateur à base de Fer, le Zerenex° qui est en fait du citrate de Fer. L’idée de chélater le phosphore avec des composés ferriques ne datent pas d’hier mais finalement peu d’études randomisées existent. Il s’agit de patients en pré-dialyse. Les critères d’inclusion sont les suivants : Hg entre 9 et 12 g/dl, la ferrtitine devait être inférieure à 300, la saturation inférieure à 30% et le phosphore entre 4 et 6 mg/dL. Les patients transfusés, traités par EPO ou pas Fer IV étaient exclus. Le traitement est administré à ds patients américains (66 ans, eGFR à 26 ml/min). L’étude est randomisée, contre placebo, « double-blinded ». Sont inclus 75 patients dans le groupe traité et 74 dans le groupe placebo (1 perdu de vue, compliance OK). L’étude porte sur une courte période de 12 semaines. Globallement, on observe une augmentation significative dans le groupe traité de la saturation en transferrine (20 à 30%), de l’hémoglobione 10.4 à 10.9 g/dl et une diminution du phosphore de 4,5 à –de 4 (les chiffres sont à considérer prudemment, c’est plus une estimation, un « trend » car les chiffres précis ne sont pas donnés mais estimés d’après les graphes présentés). De manière intéressante le FGF23 (intact et Cterminal) diminuait significativement dans le groupe traité. Le traitement parait bien supporté avec, comme c’est le cas pour tous les chélateurs, des effets secondaires surtout intestinaux (diarrhée). Aucun effet secondaire sévère n’était décrit.
Bien entendu, l’étude devra être complétée dans un plus grande population et surtout plus longtemps mais ce traitement semble faire d’ « une pierre deux coups » avec des effets bénéfiques sur l’Hg et le phosphore en prédialyse. Aucune idée du prix de la médication mais théoriquement (si on met de côté le « marketing »), cela pourrait être moins cher…
This presentation shows in CKD4-5 that iron containing chelators of phosphate reduce serum phosphorus levels and improve iron status.
This offers the dual advantage of serum Pi control and anemia management (iron repletion).
Iron containing phosphate chelators have been around for a while.
It is surprising that an iron containing chelator that is meant to be minimally absorbed improves iron stores. It would be interesting to knwo how much iron is absorbed in thse patients with advanced CKD who normally dont absorb much oral iron never mind that chelated to phosphate?
A previous study showed that iron uptake is indeed minimal in thse patients when given orla iron chelators: Median iron uptake (range) was 0.06% (0.008 - 0.44%), 0.02% (0 - 0.04%) and 0.43% (0.16% - 1.25%) in the nondialysis-dependent CKDpatients, hemodialysis patients and healthy subjects, respectively. 0.06% in CKD ND, hardly enough to correct iron stores or increase ferritin???
But the true question is:
DO WE NEED MORE PHOSPHATE BINDERS....????
PROF PIERRE DELANAYE REPORTED FROM AMSETRDAM:
PROF DELANAYE REPORTING FROM EDTA IN FRENCH AND TRANSLATED BY GOOGLE:
Dr. Roussel presented safety data on a molecule studied in type 2 diabetes : the canagliflozine (CANA ) . It is an inhibitor of the co -transporter 2 sodium / glucose . The medicament increases the excretion of glucose and results in a moderate effect of osmotic diuresis . It improves diabetic control in early studies . Some patients , however, have seen their estimated GFR decline. In this study of " safety" , the authors used ( including but not limited to ) data from six randomized trials. They looked at the number of patients who had an estimated greater than 60 ml / min at the beginning ( baseline) and DFG DFG have between 45 and 60 ml / min at the end of follow-up ( 18-26 weeks). This way is already , he seems a little questionable (why by looking at the differences in GFR ?) . In randomized trials , 262 patients on 4158 (6%) were left with a GFR < 60 ml / min. In this group the effect of the molecule on glycated hemoglobin, systolic blood pressure and weight remained beneficial, as is demonstrated if the whole sample is considered . The average decrease in GFR in 6 % patients did not differ between the placebo group and the two treatment groups. The number of side effects related to volume depletion was higher in the treated group but the number of events remained very low in absolute terms . The decrease in GFR appeared to be reversible upon discontinuation of treatment ( but not shown). 60 % had no side effects.
I 'm still not totally reassured by such a study of safety . If 6% of diabetic individuals had their GFR decreased ( it is still necessary that this reduction is statistically and clinically significant, which is not known because the slopes of GFR are not considered ), I think it would be more a useful study with a measured GFR is achieved.
The jury is still out on this new class of hypoglycemic agents.
Associated risk includes:
2. UTIs, fungal in particular
3. Bladder cancer increased risk.
4. hypotension due to hypovolemia induced by osmotic diuresis
5. Decreased GFR
6. CVD benefit versus risk?
ALTOGETHER, CAUTION SHOULD BE APPLIED WHEN CONSIDERING THESE AGENTS IN T2DM PATIENTS WITH AUTONOMIC NEUROPATHY WHO ARE PRONE TO HEMODYNAMIC INSTABILITY. FURTHERMORE, I CAN FORESEE MORE AKI INDUCED BY THE OSMOTIC DIURESIS ASSOCIATED HYPOVOLEMIA AND HYPOTENSION IN THESE PATIENT SSPECIALLY THAT MOST WILL ALSO BE ON NEPHROTOXIC ACE INHIBITORS....SCAAAAARYYYYYYY!!!!